EP0057116A2 - Insoluble polymers with controllable biodegradation, process for their production and biomaterials containing them - Google Patents

Insoluble polymers with controllable biodegradation, process for their production and biomaterials containing them Download PDF

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Publication number
EP0057116A2
EP0057116A2 EP82400028A EP82400028A EP0057116A2 EP 0057116 A2 EP0057116 A2 EP 0057116A2 EP 82400028 A EP82400028 A EP 82400028A EP 82400028 A EP82400028 A EP 82400028A EP 0057116 A2 EP0057116 A2 EP 0057116A2
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Prior art keywords
oligomer
oligomers
polymer
polymers
group
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German (de)
French (fr)
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EP0057116A3 (en
Inventor
Jean-François Fauvarque
Dominique née Juanes Dubuisson
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SERAG-WIESSNER CATGUTFABRIEKEN GmbH
LORCA MARIN SA
LIGATURES PETERS
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SERAG-WIESSNER CATGUTFABRIEKEN GmbH
LORCA MARIN SA
LIGATURES PETERS
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G79/00—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule
    • C08G79/02—Macromolecular compounds obtained by reactions forming a linkage containing atoms other than silicon, sulfur, nitrogen, oxygen, and carbon with or without the latter elements in the main chain of the macromolecule a linkage containing phosphorus
    • C08G79/04—Phosphorus linked to oxygen or to oxygen and carbon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
    • A61L17/06—At least partially resorbable materials
    • A61L17/10—At least partially resorbable materials containing macromolecular materials
    • A61L17/105—Polyesters not covered by A61L17/12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/692—Polyesters containing atoms other than carbon, hydrogen and oxygen containing phosphorus

Definitions

  • the present invention relates to new polymers with adjustable biodegradability at will, to their preparation methods and to their application as biomaterials.
  • biodegradability used in the present invention is used in the broadest sense, namely the ability for a polymer to be able to be hydrolyzed and resorbed in a biological medium, and in particular within a living organism.
  • biomaterials have uniform properties, can be sterilized, are absorbed by living tissue, are easy to handle. Their mechanical characteristics are, however, variable; more or less good knotting strength, more or less good tensile strength. Some of the biomaterials offered are difficult to wire, none of the biomaterials of the prior art has variable biodegradability and adjustable at will.
  • the oligomers OL forming the polymer are identical.
  • the oligomers forming the polymer are of different nature.
  • the oligomers are preferably chosen from the group which comprises polyethylene terephthalate (PET), and polybutylene terephthalate (PBT).
  • PET polyethylene terephthalate
  • PBT polybutylene terephthalate
  • the present invention also relates to a process for the preparation of polymers with adjustable biodegradability in accordance with the invention, characterized in that which is reacted on a bifunctional oligomer, a phosphorylating agent, and in that one proceeds to polycondensation and to the elimination of the excess of the phosphorylating agent.
  • the phosphodichloride is reacted for example on the bifunctional oligomer in at least stoichiometric quantities. to obtain the product of formula II below:
  • Y, Z and R are as defined above.
  • the phosphorylation agent forming the phosphate bridge consists of the compound of formula III below: obtained by treating cyanoethanol with a phosphorus oxytrihalogenide, according to the reaction
  • the polycondensation is carried out in a high-point solvent boiling point, the temperature, the pressure and the duration of the reaction being a function of the number of bridges capable of being hydrolyzed that it is desired to obtain.
  • the polycondensation is carried out in the presence of a catalyst taken from the group which comprises titanium tetrabutylate and antimony oxide.
  • the present invention also relates to insoluble products which can be used as biomaterials, such as threads, prostheses, dressings, obtained and shaped from polymers in accordance with the invention.
  • the present invention relates in particular to the processes for preparing polymers with variable biodegradability and adjustable at will, the polymers and the biomaterials obtained, as well as the means specific to the implementation of these processes, the overall processes and the production lines. in which are included the methods according to the present invention, as well as the objects constituted by r or containing, the polymers according to the present invention.
  • Synthesis of the oligomer the preceding mixture is poured in the molten state into the polycondensation reactor. The mixture is maintained at 285 ° C., under high vacuum, for a variable time, in order to have the desired mass oligomer.
  • Table I gives the ratio of the molecular mass Mn x obtained as a function of the operating conditions (the oligomers come from the same stock of monomers).
  • 3-Hydroxypropionitrile is added to a very large excess of phosphorus oxychloride at 0 ° C. It is maintained for two hours at 0 ° C., then the excess of POCl 3 is removed and the reagent is distilled at 30 ° C. under 0.1 mm. Yield: 40% NMR 2 triplets 2.8 ppm and 3.8 ppm. IR CN band 2250 cm -1 .
  • the product obtained in the previous example is treated with a base in a polar solvent, such as sodium tertioamylate in HMPT in stoichiometric quantity, for one hour at 80 ° C.
  • a polar solvent such as sodium tertioamylate in HMPT in stoichiometric quantity
  • the final product is precipitated by adding heptane. It is checked that in this step, the average molecular weight does not vary appreciably.

Abstract

The polymers consist of difunctional oligomers combined by bridging of the phosphate type, of general formula I <IMAGE> where: n >/= 2 OL denotes an appropriate oligomer, Y and Z denote the two functional groups of the oligomer which can be identical or different and which may be the groups OH, NH2, NR1H, R1 being a substituted or unsubstituted alkyl group, and R denotes a cation, a hydrogen atom or an alkyl, aryl or aralkyl group, substituted or otherwise. Application to the production of biomaterials such as threads, prostheses and dressings.

Description

La présente invention est relative à de nouveaux polymères à biodégradabilité réglable à volonté,à leurs procédés de préparation et à leur application en tant que biomatériaux.The present invention relates to new polymers with adjustable biodegradability at will, to their preparation methods and to their application as biomaterials.

Le terme "biodégradabilité" employé dans la présente invention,est utilisé dans le sens le plus large, à savoir la faculté pour un polymère de pouvoir être hydrolyse et résorbé dans un milieu biologique,et notamment au sein d'un organisme vivant.The term "biodegradability" used in the present invention is used in the broadest sense, namely the ability for a polymer to be able to be hydrolyzed and resorbed in a biological medium, and in particular within a living organism.

La qualité des biomatériaux utilisés dans le domaine médico-chirurgical (tels que fils pour sutures par exemple),a nettement progressé ces dernières années. Pendant très longtemps,ces fils ont été préparés à partir de catgut,lin,soie,argent,etc... Ces différents matériaux présentaient des inconvénients plus ou moins graves: s'ils étaient résorbables (comme par exemple le catgut),ils provoquaient des réactions défavorables dans l'organisme vivant, parfois même des complications graves consécutives à leurs caractéristiques antigéniques;d'autres matériaux, tels que les fils de lin,de soie ou d'argent,étaient peu ou pas du tout résorbables. Aussi, de très nombreux produits de remplacement à base de polymères synthétiques ont été proposés. Ainsi,ont été préconisés par exemple:

  • -des polymères et copolymères d'acide lactique [brevets français 1.478.694 et 1.478 695(1966)I],
  • -des polyesters de β-hydroxyacides [brevet américain 3.225.766 (1962 )],
  • -des esters polyhydroxyacétiques [brevet français 1.412.957(1966)
  • -des amino-triazoles polymères [brevet américain 3.809.683 (1973)]
  • -des copolyoxalates [brevet américain 4.141 087 (1979) et d'autres matériaux encore.
The quality of biomaterials used in the medical and surgical field (such as threads for sutures for example), has clearly improved in recent years. For a very long time, these threads were prepared from catgut, linen, silk, silver, etc. These different materials had more or less serious drawbacks: if they were absorbable (like catgut for example), they caused unfavorable reactions in the living organism, sometimes even serious complications consecutive to their antigenic characteristics; other materials, such as linen, silk or silver threads, were little or not at all absorbable. Also, a large number of replacement products based on synthetic polymers have been proposed. Thus, have been recommended for example:
  • -polymers and copolymers of lactic acid [French patents 1,478,694 and 1,478,695 (1966) I],
  • polyesters of β-hydroxy acids [American patent 3,225,766 (1962)],
  • polyhydroxyacetic esters [French patent 1,412,957 (1966)
  • - polymeric amino-triazoles [US Patent 3,809,683 (1973)]
  • copolyoxalates [US Patent 4,141,087 (1979) and other materials as well.

Ces différents biomatériaux présentent des propriétés uniformes,peuvent être stérilisés,sont absorbés par les tissus vivants,sont facilement manipulables. Leurs caractéristiques mécaniques sont toutefois variables;plus ou moins bonne solidité au nouage,plus ou moins bonne résistance à la traction. Certains des biomatériaux proposés sont difficilement filables,aucun des biomatériaux de l'art antérieur ne présente une biodégradabilité variable et réglable à volonté.These different biomaterials have uniform properties, can be sterilized, are absorbed by living tissue, are easy to handle. Their mechanical characteristics are, however, variable; more or less good knotting strength, more or less good tensile strength. Some of the biomaterials offered are difficult to wire, none of the biomaterials of the prior art has variable biodegradability and adjustable at will.

La présente invention s'est par conséquent donné pour but de pourvoir à un procédé et à un biomatériau qui répondent mieux aux nécessités de la pratique que les procédés et les biomatériaux de l'art antérieur,notamment en ce qu'ils réunissent à la fois:

  • -une très bonne faculté de filage et de façonnage,
  • -de très bonnes caractéristiques de manipulation,
  • -une très bonne solidité initiale,et la faculté de former des noeuds chirurgicaûx tenant parfaitement
  • -et une biocompatibilité totale,ainsi qu'une biodégradabilité variable et réglable à volonté.
The object of the present invention is therefore to provide a process and a biomaterial which better meet the needs of the practice than the processes and biomaterials of the prior art, in particular in that they combine both :
  • -a very good spinning and shaping ability,
  • -very good handling characteristics,
  • -a very good initial solidity, and the ability to form surgical knots holding perfectly
  • -and total biocompatibility, as well as variable and adjustable biodegradability at will.

La présente invention a pour objet des polymères insolubles à biodégradabilité réglable à volonté, caractérisés en ce qu'ils sont constitués d'oligomères bifonctionneles réunis par pontage du type phosphate de formule générale I ci-après:

Figure imgb0001
où : n ≥ 2

  • OL représente un oligomère approprié
  • Y et Z , représentent les deux fonctions de l'oligomère,lesquelles peuvent être identiques ou différentes, et qui peuvent être les groupes OH, NH2, NR1H, R étant un groupe alkyle substitué ou non, et
  • R représente un cation,un atome d'hydrogène ou un groupe alkyle, aryle ou aralkyle, substitués ou non.
The present invention relates to insoluble polymers with biodegradability adjustable at will, characterized in that they consist of bifunctional oligomers joined by bridging of the phosphate type of general formula I below:
Figure imgb0001
 where: n ≥ 2
  • OL represents an appropriate oligomer
  • Y and Z represent the two functions of the oligomer, which may be the same or different, and which may be the groups OH, NH 2 , NR 1 H, R being a substituted or unsubstituted alkyl group, and
  • R represents a cation, a hydrogen atom or an alkyl, aryl or aralkyl group, substituted or unsubstituted.

Suivant un mode de réalisation avantageux de l'objet de l'invention,les oligomères OL formant le polymère sont identiques.According to an advantageous embodiment of the subject of the invention, the oligomers OL forming the polymer are identical.

Suivant un autre mode de réalisation avantageux de l'objet de l'invention,les oligomères formant le polymère sont de nature différente.According to another advantageous embodiment of the subject of the invention, the oligomers forming the polymer are of different nature.

En alliant les ponts phosphate avec des oligomères choisis pour leurs qualités mécaniques,la demanderesse a pu réaliser des polymères biodégradables de qualité exceptionnelle,satisfaisant à tous les critères exigibles des polymères utilisés dans un domaine aussi délicat qu'est le domaine médico- chirurgical.By combining phosphate bridges with oligomers chosen for their mechanical qualities, the Applicant has been able to produce biodegradable polymers of exceptional quality, satisfying all the criteria required of polymers used in a field as delicate as the medical-surgical field.

Conformément à l'invention,les oligomères sont choisis de préférence dans le groupe qui comprend le polyéthylène-téréphtalate (PET),et le polybutylènetéréphtalate (PBT).According to the invention, the oligomers are preferably chosen from the group which comprises polyethylene terephthalate (PET), and polybutylene terephthalate (PBT).

La présente invention a également pour objet un procédé de préparation des polymères à biodégradabilité réglable conformes à l'invention,caractérisé en ce qu'on fait réagir sur un oligomère bifonctionnel,un agent de phosphorylation,et en ce qu'on procède à la polycondensation et à l'élimination de l'excès de l'agent de phosphorylation.The present invention also relates to a process for the preparation of polymers with adjustable biodegradability in accordance with the invention, characterized in that which is reacted on a bifunctional oligomer, a phosphorylating agent, and in that one proceeds to polycondensation and to the elimination of the excess of the phosphorylating agent.

Conformément à l'invention,on fait par exemple réagir sur l'oligomère bifonctionnel en quantités au moins stoechiométriques,le phosphodichlorure

Figure imgb0002
pour obtenir le produit de formule II ci-après:
Figure imgb0003
 In accordance with the invention, the phosphodichloride is reacted for example on the bifunctional oligomer in at least stoichiometric quantities.
Figure imgb0002
 to obtain the product of formula II below:
Figure imgb0003

Y, Z et R sont tels que définis précédemment..Y, Z and R are as defined above.

Suivant un mode de réalisation avantageux de l'objet de l'invention, l'agent de phosphorylation formant le pont phosphate est constitué par le composé de formule III ci-après:

Figure imgb0004
obtenu en traitant le cyanoéthanol par un oxytrihalo- génure de phosphore,suivant la réaction
Figure imgb0005
 According to an advantageous embodiment of the subject of the invention, the phosphorylation agent forming the phosphate bridge consists of the compound of formula III below:
Figure imgb0004
 obtained by treating cyanoethanol with a phosphorus oxytrihalogenide, according to the reaction
Figure imgb0005

Il suffit de remplacer ensuite le groupe -CH2-CH2-CN par un groupe R convenablement choisi(le choix de R dépendant du degré et de la rapidité d'hydrolyse et de résorption désirés.It then suffices to replace the group -CH 2 -CH 2 -CN with a group R suitably chosen (the choice of R depending on the degree and the speed of hydrolysis and resorption desired.

Suivant un mode de réalisation avantageux de procédé objet de la présente invention,la polycondensation est effectuée dans un solvant à haut point d'ébullition, la température, la pression et la durée de la réaction étant fonction du nombre de ponts susceptibles d'être hydrolysés que l'on désire obtenir.According to an advantageous embodiment of the process which is the subject of the present invention, the polycondensation is carried out in a high-point solvent boiling point, the temperature, the pressure and the duration of the reaction being a function of the number of bridges capable of being hydrolyzed that it is desired to obtain.

Suivant une modalité particulière de ce mode de réalisation,la polycondensation est effectuée en présence d'un catalyseur pris dans le groupe qui comprend le tétrabutylate de titane et l'oxyde d'antimoine.According to a particular embodiment of this embodiment, the polycondensation is carried out in the presence of a catalyst taken from the group which comprises titanium tetrabutylate and antimony oxide.

La présente invention. a également pour objet,les produits insolubles utilisables en tant que biomatériaux, tels que fils, prothèses,pansements,obtenues et façonnés à partir de polymères conformes à l'invention.The present invention. also relates to insoluble products which can be used as biomaterials, such as threads, prostheses, dressings, obtained and shaped from polymers in accordance with the invention.

Outre les dispositions qui précèdent,l'invention comprend encore d'autres dispositions,qui ressortiront de la description qui va suivre.In addition to the foregoing provisions, the invention also comprises other provisions, which will emerge from the description which follows.

La présente invention vise particulièrement les procédés de préparation de polymères à biodégradabilité variable et réglable à volonté, les polymères et les biomatériaux obtenus,ainsi que les moyens propres à la mise en oeuvre de ces procédés,Ies procédés d'ensemble et les chaînes de fabrication dans lesquels sont inclus les procédés conformes à la présente invention,de même que les objets constitués parr ou contenant,les polymères conformes à la présente invention.The present invention relates in particular to the processes for preparing polymers with variable biodegradability and adjustable at will, the polymers and the biomaterials obtained, as well as the means specific to the implementation of these processes, the overall processes and the production lines. in which are included the methods according to the present invention, as well as the objects constituted by r or containing, the polymers according to the present invention.

L'invention pourra être mieux comprises à l'aide du complément de description qui va suivre,qui se réfère à des exemples de. préparation et à des caractéristiques de polymères conformes à la présente invention.The invention may be better understood with the aid of the additional description which follows, which refers to examples of. preparation and characteristics of polymers in accordance with the present invention.

Il doit être bien entendu, toutefois, que les différents exemples et caractéristiques sont donnés uniquement à titre d'illustration de l'objet de l'invention,mais n'en constituent en aucune manière une limitation.It should be understood, however, that the various examples and characteristics are given solely by way of illustration of the subject of the invention, but do not in any way constitute a limitation thereof.

EXEMPLE 1- SYNTHESE DES OLIGOMERES(PET)EXAMPLE 1- SYNTHESIS OF OLIGOMERS (PET)

Synthèse du monomère: dans un ballon tricol de 500 cm ,on mélange 105g de diméthyltéréphtalate recristallisé dans le méthanol,150g d'éthylèneglycol distillé sur sodium,155 mg d'acétate de calcium et 20 cm3 de méthanol. 0n monte la température à 140-150fC sous azote en 30 minutes et on maintient à cette température pendant 30 minutes. On chauffe ensuite le mélange à 180°C pendant 4 heures. On élimine l'excès d'éthylèneglycol par distillation. On laisse refroidir,on ajoute un catalyseur et on chauffe sous agitation pour homogénéiser.Synthesis of the monomer: in a 500 cm three-necked flask, 105 g of dimethyl terephthalate recrystallized from methanol, 150 g of ethylene glycol distilled over sodium, 155 mg of calcium acetate and 20 cm 3 of methanol are mixed. The temperature is raised to 140-150fC under nitrogen in 30 minutes and maintained at this temperature for 30 minutes. The mixture is then heated at 180 ° C for 4 hours. The excess ethylene glycol is removed by distillation. The mixture is allowed to cool, a catalyst is added and the mixture is heated with stirring to homogenize.

Synthèse de l'oligomère: on coule le mélange précédent à l'état fondu dans le réacteur de polycondensation. On maintient le mélange à 285°C,sous vide poussé,pendant un temps variable, pour avoir l'oligomère de masse voulue.Synthesis of the oligomer: the preceding mixture is poured in the molten state into the polycondensation reactor. The mixture is maintained at 285 ° C., under high vacuum, for a variable time, in order to have the desired mass oligomer.

Le tableau I ci-dessous donne le rapport de la masse moléculaire Mnx obtenue en fonction des conditions opératoires (les oligomères proviennent du même stock de monomères).

Figure imgb0006
Table I below gives the ratio of the molecular mass Mn x obtained as a function of the operating conditions (the oligomers come from the same stock of monomers).
Figure imgb0006

EXEMPLE 2-SYNTHESE DU CYANOETHYLPHOSPHODICHLORUREEXAMPLE 2 SYNTHESIS OF CYANOETHYLPHOSPHODICHLORIDE

On ajoute le 3-hydroxypropionitrile à un très large excès d'oxychlorure de phosphore à 0°C. On maintient deux heures à 0°C,puis on élimine l'excès de POCl3 et on distille le réactif à 30°C sous 0,1 mm. Rendement : 40% RMN 2 triplets 2,8 ppm et 3,8 ppm. IR Bande CN 2250 cm-1.3-Hydroxypropionitrile is added to a very large excess of phosphorus oxychloride at 0 ° C. It is maintained for two hours at 0 ° C., then the excess of POCl 3 is removed and the reagent is distilled at 30 ° C. under 0.1 mm. Yield: 40% NMR 2 triplets 2.8 ppm and 3.8 ppm. IR CN band 2250 cm -1 .

EXEMPLE 3-SYNTHESE DE PET RELIES PAR DES PONTS CYANOETHYLPHOSPHATEEXAMPLE 3 SYNTHESIS OF PET CONNECTED BY CYANOETHYLPHOSPHATE BRIDGES

60g d'oligomère polyéthylènetéréphtalate (Mn= 2300)sont traités par 11,5 g de cyanoéthylphos- phodichlorure une nuit à 80°C, puis 7 heures sous 30 mm de Hg à 90°C. On filtre le solvant et on sèche le TEP diphosphoryle. On ajoute un solvant lourd tel que le bromonaphtalène et on procède à la polycondensation dans un tube à 270°C pendant une heure sous vide progressif jusqu'à 20 mm de Hg, puis pendant 3 h 30 sous 0,1 mm de Hg. On obtient un polymère de Mn = 22000.60 g of polyethylene terephthalate oligomer (Mn = 2300) are treated with 11.5 g of cyanoethylphosphodichloride overnight at 80 ° C., then 7 hours under 30 mm Hg at 90 ° C. The solvent is filtered and the diphosphorylated TEP is dried. Adding a heavy solvent such as bromonaphtal ene and the polycondensation is carried out in a tube at 270 ° C for one hour under gradual vacuum to 20 mm Hg, then 30 for 3 hours under 0.1 mm Hg A polymer of Mn = 22000 is obtained.

Spectre RMN 31P 1 pic à 1,65 ppm. 31 P NMR spectrum 1 peak at 1.65 ppm.

Un polymère de ce type a été filé. Pour Mn=13000, la résistance à la traction est supérieure à 10g pour un diamètre de 80 µ.A polymer of this type was spun. For Mn = 13000, the tensile strength is greater than 10g for a diameter of 80 µ.

EXEMPLE 4-SYNTHESE DE PET RELIES PAR DES PONTS PHOSPHATE SEL DE SODIUMEXAMPLE 4 SYNTHESIS OF PET CONNECTED BY SODIUM SALT PHOSPHATE BRIDGES

Le produit obtenu dans l'exemple précédent, est traité par une base dans un solvant polaire,tel que le tertioamylate de sodium dans l'HMPT en quantité stoechiométrique,pendant une heure à 80°C. Le produit final est précipité par addition d'heptane. On vérifie que dans cette étape,la masse moléculaire moyenne ne varie pas sensiblement.The product obtained in the previous example is treated with a base in a polar solvent, such as sodium tertioamylate in HMPT in stoichiometric quantity, for one hour at 80 ° C. The final product is precipitated by adding heptane. It is checked that in this step, the average molecular weight does not vary appreciably.

Figure imgb0007
Figure imgb0007

Ainsi que cela ressort de ce qui précède,l'invention ne se limite nullement à ceux de ses modes de mise en oeuvre,de réalisation et d'application qui viennent d'être décrits de façon plus explicite;elle en embrasse au contraire toutes les variantes qui peuvent venir à l'esprit du technicien en la matière, sans s'écarter du cadre,ni de la portée de la présente invention.As is apparent from the above, the invention is in no way limited to those of its modes of implementation, embodiment and application which have just been described in a more explicit manner; on the contrary, it embraces all of them. variants which may come to the mind of the technician in the field, without departing from the scope or the scope of the present invention.

Claims (9)

1.Polymères à biodégradabilité réglable à volonté,caractérisés en ce qu'ils sont constitués d'oligomères bifonctionnels réunis par pontage du type phosphate,de formule générale I
Figure imgb0008
où= n > 2 OL représente un oligomère approprié Y et Z représentent les deux fonctions de l'oligomère,lesquelles peuvent être identiques ou différentes,et qui peuvent être les groupes OH,NH2, NR1H, R1 étant un groupe alkyle substitué ou non, et R représente un cation,un atome d'hydrogène ou un groupe alkyle,aryle ou aralkyle,substitués ou non. 1. Polymers with biodegradability adjustable at will, characterized in that they consist of bifunctional oligomers joined by bridging of the phosphate type, of general formula I
Figure imgb0008
 where = n> 2 OL represents an appropriate oligomer Y and Z represent the two functions of the oligomer, which may be the same or different, and which may be the groups OH, NH 2 , NR 1 H, R 1 being a substituted or unsubstituted alkyl group, and R represents a cation, a hydrogen atom or an alkyl, aryl or aralkyl group, substituted or unsubstituted. Z.Polymère selon la revendication 1,caractérisé en ce que les oligomères OL formant le polymère,sont identiques.Z.Polymer according to claim 1, characterized in that the oligomers OL forming the polymer are identical. 3.Polymère selon la revendication l,caractérisé en ce que les oligomères formant le polymère,sont de nature différente.3. Polymer according to claim l, characterized in that the oligomers forming the polymer are of different nature. 4. Polymère selon l'une quelconque des revendications 1 à 3,caractérisé en ce que les oligomères sont choisis dans le groupe qui comprend le polyéthylène- téréphtalate (PET) et le polybutylènetéréphtalate (PBT).4. Polymer according to any one of claims 1 to 3, characterized in that the oligomers are chosen from the group which comprises polyethylene terephthalate (PET) and polybutylene terephthalate (PBT). 5. Procédé de préparation des polymères selon l'une quelconque des revendications 1 à 4,caractérisé en ce qu'on fait réagir sur un oligomère bifonctionnel,un agent de phosphorylation et en ce qu'on procède à la polycondensation et à l'élimination de l'excès de l'agent de phosphorylation.5. Process for the preparation of polymers according to any one of claims 1 to 4, characterized in that one reacts on a bifunctional oligomer, a phosphorylation agent and in that one proceeds to polycondensation and elimination of the excess phosphorylating agent. 6.Procédé selon la revendication S,caractérisé en ce qu'on fait réagir sur l'oligomère bifonctionnel,en des quantités au moins stoechiométriques, le phosphodichlorure
Figure imgb0009
pour obtenir le produit de formule II ci-après:
Figure imgb0010
ou: Y, Z et R sont tels que définis précédemment. 6. Process according to claim S, characterized in that the phosphodichloride is reacted on the bifunctional oligomer, in at least stoichiometric quantities.
Figure imgb0009
 to obtain the product of formula II below:
Figure imgb0010
 or: Y, Z and R are as defined above. 7.Procédé selon la revendication 5,caractérisé en ce que l'agent de phosphorylation formant le pont phosphate est constitué par le composé de formule III ci-après:
Figure imgb0011
obtenu en traitant le cyanoéthanol par un oxytrihalo- génure de phosphate,suivant la réaction:
Figure imgb0012
 7. Method according to claim 5, characterized in that the phosphorylation agent forming the phosphate bridge consists of the compound of formula III below:
Figure imgb0011
 obtained by treating cyanoethanol with a phosphate oxytrihalogenide, according to the reaction:
Figure imgb0012
 8.Procédé selon l'une quelconque des revendications 5 à 7,caractérisé en ce que la polycondensation est effectuée en présence d'un catalyseur pris dans le groupe qui comprend le tétrabutylate de titane et l'oxyde d'antimoine.8. Process according to any one of claims 5 to 7, characterized in that the polycondensation is carried out in the presence of a catalyst taken from the group which comprises titanium tetrabutylate and antimony oxide. 9.Biomatériaux,tels que fils,prothèses et pansements,caractérisés en ce qu'ils comprennent des polymères selon l'une quelconque des revendications 1 à 4.9. Biomaterials, such as threads, prostheses and dressings, characterized in that they comprise polymers according to any one of claims 1 to 4.
EP82400028A 1981-01-26 1982-01-08 Insoluble polymers with controllable biodegradation, process for their production and biomaterials containing them Withdrawn EP0057116A3 (en)

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FR8101400 1981-01-26

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WO1998044021A1 (en) * 1997-04-03 1998-10-08 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly(phosphate) polymers, compositions, articles, and methods for making and using the same
US6153212A (en) * 1998-10-02 2000-11-28 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly (phosphonate) compositions, articles, and methods of using the same
US6350464B1 (en) 1999-01-11 2002-02-26 Guilford Pharmaceuticals, Inc. Methods for treating ovarian cancer, poly (phosphoester) compositions, and biodegradable articles for same
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US4792599A (en) * 1986-01-28 1988-12-20 Biocompatibles Ltd. Biocompatible polyesters
WO1988000956A1 (en) * 1986-07-28 1988-02-11 Biocompatibles Limited Polyesters
WO1998044021A1 (en) * 1997-04-03 1998-10-08 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly(phosphate) polymers, compositions, articles, and methods for making and using the same
US6600010B2 (en) 1997-04-03 2003-07-29 Guilford Pharmaceuticals, Inc. Biodegradable terephthalate polyester-poly (phosphate) polymers, compositions, articles, and methods for making and using the same
AU741145B2 (en) * 1997-04-03 2001-11-22 Eisai Inc. Biodegradable terephthalate polyester-poly(phosphate) polymers, compositions, articles, and methods for making and using the same
US6322797B1 (en) 1997-04-03 2001-11-27 Guilford Pharmaceuticals, Inc. Biodegradable terephthalate polyester-poly (phosphate) polymers, compositions, articles, and methods for making and using the same
AU749644B2 (en) * 1997-04-30 2002-06-27 Guilford Pharmaceuticals Inc. Biodegradable compositions comprising poly(cycloaliphatic phosphoester) compounds, articles, and methods for using the same
US6485737B1 (en) 1998-10-02 2002-11-26 Guilford Pharmaceuticals, Inc. Biodegradable terephthalate polyester-poly (phosphonate) compositions, articles and methods of using the same
US6153212A (en) * 1998-10-02 2000-11-28 Guilford Pharmaceuticals Inc. Biodegradable terephthalate polyester-poly (phosphonate) compositions, articles, and methods of using the same
US6479067B2 (en) 1999-01-11 2002-11-12 Guilford Pharmaceuticals, Inc. Methods for treating ovarian cancer, poly (phosphoester) compositions, and biodegradable articles for same
US6350464B1 (en) 1999-01-11 2002-02-26 Guilford Pharmaceuticals, Inc. Methods for treating ovarian cancer, poly (phosphoester) compositions, and biodegradable articles for same
US6641833B2 (en) 1999-01-11 2003-11-04 Guilford Pharmaceuticals, Inc. Methods for treating ovarian cancer, poly (phosphoester) compositions, and biodegradable articles for same
US6537585B1 (en) 1999-03-26 2003-03-25 Guilford Pharmaceuticals, Inc. Methods and compositions for treating solid tumors
US7101568B2 (en) 1999-03-26 2006-09-05 Guilford Pharmaceuticals, Inc. Methods and compositions for treating solid tumors

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